JP2002249446A - Medicine for multidrug combined use effective for cure of impotence - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicine for multidrug combined use to cure impotence (male erection deficiency) especially in human being. SOLUTION: A compound (1) selected from potassium channel openers and a compound (2) selected from compounds to raise a cGMP level are used for this medicine for multidrug combined use. In this case, sildenafil or its pharmaceutically allowable salt is preferable as a cGMP raiser.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to a method comprising the steps of co-administering (1) a potassium channel opener and (2) a compound that increases cyclic guanosine 3 ', 5'-monophosphate (cGMP) levels. Regarding treatment. The combination is particularly suitable for treating patients suffering from disability or erectile dysfunction.

[0002]

The inability to achieve and / or sustain an erection sufficient for vaginal penetration and / or sexual intercourse is the impossibility. Accordingly, disability is also called {erectile dysfunction} or {erectile dysfunction}. It is estimated that 10-12 million American men aged 18 to 75 are suffering from chronic disability, most of whom are over 55 years old.

[0003] Certain tissues in the central part of the penis, particularly the corpus cavernosum, are filled with blood, thereby becoming less tender.
The penis usually erects when it causes erections sequentially.
Impossibility is psychological disorder (psychogenic), physiological abnormality (organic)
Or it may be due to a combination of both. Thus, some male erectile dysfunction may be due to anxiety or depression without apparent physical or organic impairment. In another case, erectile dysfunction is associated with atherosclerosis of the arteries that supply blood to the penis. In yet another case, the dysfunction may be due to a venous leak or abnormal outflow with leaks from the penile vein that cannot and cannot maintain enough pressure for an erection. Absent. In yet another case,
Dysfunction is associated with neuropathy or due to nerve damage resulting from, for example, surgery or pelvic injury.
Typically, several factors are involved in the impairment.

[0004] Pharmacological, biophysical and molecular studies have shown multiple subtypes of membrane ion channels that form potassium-selective pores in the plasma membrane of many mammalian cells. Simply, the family of K channels can be classified according to each entry characteristic. In other words, a comparison of the pharmacological and electrophysiological properties of potassium channels has yielded an operational definition for classifying various subtypes based primarily on entry properties. At present, the known amino acid sequences of potassium channels constitute two distantly related protein families. One of these channel families is called {potential-dependent} and the other channel family is called {inward rectification}.

[0005] The structure of voltage-gated channel proteins is known to consist of six transmembrane domains in each subunit, each controlled by changes in membrane potential. B. Hill (B. Hille) {Ion channels of excitable membranes} (Sinauer, Sunderland, Mass., 1992). Voltage-gated potassium channels sense changes in membrane potential and move potassium ions in response to this change in cell membrane potential. Molecular cloning studies on potassium channel proteins have mainly gained information on members of the voltage-dependent family of potassium channels. Various genes encoding these voltage-dependent families of potassium channel proteins have been identified by Shaker and Shaw.
And Shab loci; Way A. (Wei
A.) and the like, Science (1990) Vol. 248 pp. Was cloned using Drosophila genes derived from both 599-603.

[0006] Unlike voltage-gated channel proteins having six transmembrane domains, the inward rectifier channel has only two transmembrane domains, each of which is sensitive to a net change in potassium concentration. Among this class of channels are ATP-sensitive potassium channels. These channels are classified by their sensitivity to the concentration flux of ATP. ATP-sensitive or ATP-dependent potassium channels are an important class of channels that link the bioenergetic status of cells to changes in cell function. These channels are blocked by high intracellular ATP concentrations and open when ATP decreases. Lazdunski (1992); Rasunski, etc., AT
P-sensitive K <+> channel II, Renal Physiol. Bioche
m. Vol.17: pp. 118-120 (1994).

[0007] ATP-dependent potassium channels were originally described in heart tissue (Noma A., Nature (1983) Vol. 305 pp. 147-14).
8) followed by pancreatic beta cells (Cook et al., Natur
e (1984) Vol. 311 pp. 271-273), smooth muscle of blood vessels (Nelson MT, etc.), am. J. Physiol.
990) Vol. 259 pp. C3-C18) and the thick ascending limb of the kidney (Wang W., et al., Am. J. Physiol. (1990) V
ol. 258, pp. F244-F-253).

[0008] ATP-sensitive or ATP-dependent potassium channels play important roles in human physiology. Like other potassium channels, ATP-sensitive potassium channels selectively control the permeability of cells to potassium ions. These channels function to control smooth muscle contraction and relaxation by opening or closing channels in response to modulation of receptors or potentials on cell membranes. When the ATP-sensitive potassium channel is opened, the increased permeability of the cell membrane shifts more potassium ions outward, so that the membrane potential shifts to more negative values. If the membrane potential shifts toward more negative values, the calcium channel opens more and less as the membrane potential becomes more negative, thus reducing the opening of voltage-gated calcium channels, Reduces the entry of calcium ions into cells. Thus, drugs with ATP-sensitive potassium channel opening activity, ie, drugs known as potassium channel openers, can relax vascular smooth muscle and are useful as antihypertensives and coronary vasodilators.

[0009] A relatively large number of compounds that open ATP-sensitive potassium channels, especially in the cell membranes of smooth muscle, are now known, and minoxidil sulfate, diazoxide and nicorandil are well-known potassium channel openers. The target site for these drugs is probably on the potassium channel itself, but may also be on related regulatory proteins.

[0010] Potassium channel openers represent a diverse series of compounds that have a reported effect of opening only one subset of the channels allegedly sensitive to ATP. As explained above, these compounds provoke a physiological response by increasing the membrane permeability to potassium,
It results in hyperpolarization of the cell membrane and temporary desensitization to electrical and chemical stimuli.

Openers targeting these channels have been synthesized as potential drugs in hypertension, angina, coronary heart disease, asthma and urinary incontinence. There are various references describing potassium channel openers: Cook et al., {Kalium Channels: Structure, Classification, Function and Therapeutic Potential}, ed. NS Co
ok, Ellis Horwood, Chichester (1990), pp. 181-255;
David W. Robertson (David W. Robertson), etc.
Journal of Medicinal Chemistry, {Potassium Channel Modulators: Scientific Applications and Therapeutic Potential},
vol. 33, No. 6, Jun. 1990, pp. 1529-1541; Gillian Edwards et al., “K-channel opener structure-activity relationship”, vol. 11, No. 10, Oct.
1990, pp. 417-422; Valerie A. Ashwood (Valeri
e A. Ashwood) et al., {Synthesis and Antihypertensive Activity of Pyran Oxygen and Amide Nitrogen Substituted Analogs of the Potassium Channel Activator Cromakalim}, Journal of Medicinal Chemistr
y, vol. 34, No. 11, Nov. 1991, pp. 3261-3267; Longman (Susan D. Longman) et al. {Activators of potassium channels: mechanism of action, pharmacological properties and therapeutic potential}, Medicinal Research Reviews, v
ol. 12, No. 2, Mar. 1, 1992, pp. 73-148; Atwar (Karnail S. Atwal), カ リ ウ ム Modulation of potassium channels by biomolecules ゛, Med
icinal Research Reviews, vol. 12, No. 6, Nov. 199
2, pp. 569-591.

[0012] Drugs that raise cGMP levels are also well known and can act through any of several mechanisms. Enzymes mainly involved in cGMP degradation, such as cGMP phosphodiesterase (cGMP
Drugs that selectively inhibit MP PDE) constitute an example. Other phosphodiesterases can also hydrolyze cGMP, and inhibitors of these enzymes, including compounds such as rolipram, zaprinast and xanthine derivatives such as caffeine, theophylline and theobromine, may thus affect cGMP levels. . cGM
Other compounds that increase P levels are either directly or indirectly, as in the case of atrial natriuretic peptide, through different mechanisms, including activation of soluble or membrane-bound guanylate cyclase. , You can do so. Other compounds have been shown to modulate cellular cGMP by modulating cytokines.
Acts to increase the level. Another class of cGMP elevating agents includes muscarinic agonists that can increase cGMP levels without altering phosphodiesterase activity. Some of prostaglandins Jill, such as PGE ₁ are also known cGMP
It is a raising agent. Kanba et al., J. Neurochem., Vol.
57, No. 6, 1991.

[0013] Cyclic guanosine 3 ', 5'-monophosphate phosphodiesterase (cGMP PDE) inhibitors are widely known as cardiovascular drugs for the treatment of conditions such as angina, hypertension and congestive heart failure.
More recently, cGMP PDE inhibitors have been shown to be effective in the treatment of impotence, although it is important to do so by oral administration. See, for example, PCT / EP94 / 01580 published as WO94 / 28902. It is believed that such compounds can achieve high cGMP levels through inhibition of phosphodiesterase, thereby relaxing and expanding the corpus cavernosum and exerting a therapeutic effect by blocking the outflow of blood from the penis.

[0014]

SUMMARY OF THE INVENTION The present invention provides an effective amount for a patient in need of such treatment: (1) a compound selected from potassium channel openers (also referred to as potassium channel activators); (2) It is known in the art as impossibility (also referred to as {male erectile dysfunction}), particularly in humans, including co-administration of a compound that increases cGMP levels (also referred to herein as a cGMP elevating agent). (Referred to herein) are provided.

The potassium channel openers and / or c in both the present disclosure and the appended claims
When referring to a compound or drug within the scope of (1) or (2) above, such as a GMP-elevating agent, at any time all such drugs, including their free forms (eg, free acid or base forms), are included. And all pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, isomers, stereoisomers (eg, diastereomers and enantiomers) and Naturally, a mutant or the like is included. Also included are active metabolites of any form of potassium channel opener or cGMP-elevating agent.

As a cGMP elevating agent, cGMP PDE
Inhibitors are preferred. Cyclic adenosine 3 ',
5'-monophosphate phosphodiesterase (cAMP PD
Particularly preferred are cGMP PDE inhibitors which are selective for cGMP PDE rather than E) and / or which are selective inhibitors of cGMP PDE _V isoenzyme. Such particularly preferred cGMP PDE inhibitors are described in U.S. Patent Nos. 5,250,534, 5,346,901,5,
No. 272,147 and, inter alia, W specifying the United States.
These are disclosed in international patent applications published as O94 / 28902, each of which is incorporated herein by reference.

A preferred combination drug of a potassium channel opener and a cGMP elevating agent useful herein is that the co-administration of a compound selected from the above (1) and (2) has a therapeutic effect greater than the sum. Is synergistic. Thus, co-administration of both therapeutic agents produces an effect that is greater than the sum of the effects of each drug alone. Such synergy is advantageous in that it allows each therapeutic agent to be administered, typically in smaller amounts than if the combined therapeutic effects were additive. Thus, for example, treatment of a patient who does not respond well to one component used at a dose considered to be of the greatest strength can be achieved. In addition, side effects, such as priapism or pain at the site of injection, are often minimized or avoided by administering lower amounts of the components than when the combined effect is additive. it can. Such synergy can be demonstrated by the tests disclosed below.

The synergistic effect of such preferred combination drugs is provided as a further feature of the present invention, and thus the present invention relates to the use of (1) potassium channel openers in mammals in need of such treatment. And (2) a fixed amount of a second compound selected from compounds that increase the cGMP level (wherein a fixed amount of the first compound alone and a fixed amount of the second compound, respectively) While alone is insufficient to achieve a therapeutically effective level of inability to treat synergism, the combined effect of a given amount of the first and second compounds will result in separate amounts of the first and second compounds. A greater than the sum of the levels of therapeutic effect of the disability treatment achievable with the compound of the formula (I).

Further preferred multi-drug combinations include those which can be used {on demand} as opposed to the need to use them regularly. Such preferred multi-drug combinations include those in which the patient responds to a sexual (eg, visual) stimulus, as opposed to a composition that works by erecting without sexual stimulation. That change

More preferred combination drugs include those in which the time from administration to the point in time at which the sexual response can be altered is less than about 2 hours, preferably less than about 1 hour, more preferably on the order of half an hour or less. , Which preferably act within 10 to 15 minutes.

In the present disclosure and the appended claims, for example, when used in connection with a multidrug combination of a potassium channel opener and a cGMP PDE inhibitor, {co-administration} means that the route of administration of each component is the same. Means that the individual components can be administered together as a single composition. Accordingly, the present invention further provides: (1) a first compound, wherein the first compound is selected from potassium channel openers; (2) a second compound that increases cGMP levels; and (3) pharmaceutically acceptable. A composition comprising an excipient, diluent or carrier that can be used. A preferred group of compositions is synergistic. Such synergistic compositions provided as a further feature of the invention include: (1) a fixed amount of a first compound selected from potassium channel openers; (2) a fixed amount selected from compounds that increase cGMP levels. An amount of the second compound (where a predetermined amount of the first compound alone and a predetermined amount of the second compound alone, respectively, are insufficient to achieve a therapeutically effective level of inability to treat synergy. But the effect of a composition comprising this amount of the first and second compounds is greater than the sum of the levels of therapeutic effect of the disability treatment achievable with the individual amounts of the first and second compounds); And a pharmaceutically acceptable excipient, diluent or carrier.

[0022] "Co-administration" also includes administering compounds (1) and (2) separately but as part of the same therapeutic treatment program or regimen, at different times and different routes. May be recommended at times. Thus, the two compounds need not necessarily be administered at the same time or in any order. In a preferred embodiment,
Dosing will result in a peak pharmacokinetic effect of one compound,
The time is set to match the pharmacokinetic effect of the other peak. When co-administered separately, it is also preferable to administer both compounds (1) and (2) in oral dosage form.

In the present specification, the term "multidrug" refers to a compound selected from (1) as defined above, either as a single composition or separately, for example, by different administration routes. And (2).

The compositions of the present invention are also useful for treating sexual dysfunction in female mammals, including humans. Therefore,
The compositions are useful for treating female sexual dysfunction, including, for example, orgasmic dysfunction associated with clitoral disorders. Compositions that are synergistic, can be used on demand, and alter the female sexual response, as in male mammals, are preferred. Preferred compounds, compositions, and combination drugs for the treatment of female sexual dysfunction (eg,
Compounds for separate administration) are the same as those disclosed herein for the treatment of male erectile dysfunction.

Treatment of female sexual dysfunction is similar to that presented herein for the treatment of disability or erectile dysfunction in male animals.

The present invention has aspects related to the treatment of inability or female sexual dysfunction due to the treatment of compounds that can be co-administered separately with a multidrug combination. It also relates to the combined separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions:
(1) a composition comprising a compound selected from potassium channel openers, and a pharmaceutically acceptable excipient, diluent or carrier; and (2) a compound selected from a drug that increases cGMP levels, and pharmacy. And compositions containing excipients, diluents or carriers that are acceptable in nature and containers. The amounts of (1) and (2) are such that when co-administered separately, they treat and / or cure a disabled condition or a condition of female sexual dysfunction. The kit includes a separate composition, such as a container, a divided bottle or a divided foil package, in each partition containing a plurality of dosage forms (eg, tablets) containing (1) or (2). Including parts. Alternatively, rather than isolating the dosage form containing the active ingredient, the kit may, in turn, have separate partitions each containing the entire amount that constitutes a separate dosage form. One example of a kit of this type is that one (or more) first tablet contains the pharmaceutical composition (1) and the second (or more) tablet contains the pharmaceutical composition (2). Or more) in each blister. Typically, the kit includes instructions for administration of the separate components. The kit form may be used when the separate components are preferably administered in different dosage forms (eg, oral and parenteral), at different dose intervals, or when the titer of the individual components of the combination drug is increased. It is particularly advantageous if desired by the prescribing physician. In the case of the present invention, the kit therefore comprises a therapeutically effective amount of (1) a compound selected from potassium channel openers, and a pharmaceutically acceptable excipient, A composition comprising an agent or carrier; (2) a second dosage form comprising a compound selected from compounds that increase cGMP levels, and a pharmaceutically acceptable excipient, diluent or carrier. , A composition; and (3) a container for containing these first and second dosage forms.

One example of a kit as mentioned above is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms such as tablets and capsules. Blister packs usually consist of a sheet of relatively hard material, preferably covered with a foil of a transparent plastic material. During the packaging process,
A depression is formed in the plastic foil. The depression has the size and shape of the tablet or capsule to be packaged. Next, the tablets or capsules are placed in the depressions and a sheet of relatively hard material is sealed against the plastic foil with the foil surface opposite the direction in which the depressions were formed. As a result, the tablets or capsules are sealed in the depression between the plastic foil and the sheet. Preferably, the strength of the sheet is such that tablets or capsules can be removed from the blister pack by the opening of the sheet at the location of the depression by manual pressure applied to the depression. The tablets or capsules can then be removed through this opening.

[0028] For example, in the form of a number next to the tablets or capsules corresponding to the number of days of the regimen to take the tablets or capsules so designated, a memory aid is provided on the kit. It may be desirable to do so. Another example of such a memory aid would be, for example, printed on cards such as {1st week, Monday, Tuesday, etc.}, 2nd week, Monday, Tuesday, ...}, etc. It is a calendar. Other variations that help with memory are readily apparent. The "daily dose" may be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, the daily dose of the first compound may consist of one tablet or capsule, while the daily dose of the second compound may consist of several tablets or capsules, and The reverse is also acceptable. Anything that helps with memory should reflect this.

Further, potassium channel opener / c
Other pharmaceutical ingredients may optionally be included as part of a useful combination drug of the present invention, as long as they do not interfere with or adversely affect the effects of the GMP-elevating drug combination.

The preferred combination drug further includes (1) cG
Suitable potent potassium channel openers such as MP PDE inhibitors and nicorandil; and (2) cGMP PD which is selective for PDE _V isoenzymes
Contains E inhibitors. Compounds that are selective for PDE _V isoenzymes are disclosed, for example, in PCT / EP94 / 01580 published as WO 94/28902, which specifically designates the United States and is hereby incorporated by reference.

Preferred cGMP PDE inhibitors include those having the structure:

Embedded image And a pharmaceutically acceptable salt thereof, and the structure:

Embedded image And pharmaceutically acceptable salts thereof. Second compounds are disclosed, for example, in US Pat. Nos. 5,272,147 and 5,426,107, both of which are incorporated herein by reference.

Other preferred cGMP PDE inhibitors include 3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl] -2 -(Pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4
3-d] pyrimidin-7-one; 3-ethyl-5- [5
-(4-ethylpiperazin-1-ylsulfonyl)-
2) 2-Methoxyethoxy) pyridin-3-yl] -2
-(Pyridin-2-yl) methyl-2,6-dihydro-
7H-pyrazolo [4,3-d] pyrimidin-7-one;
3-ethyl-5- [5- (4-ethyl-4-oxidepiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridine-2
-Yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- [2- (2
-Methoxyethoxy) -5- (4-methylpiperazine-
1-ylsulfonyl) pyridin-3-yl] -3-n-
Propyl-2- (pyridin-2-yl) methyl-2,6
-Dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- [5- (4-ethylpiperazine-1-
Ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -3-n-propyl-2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3- d] pyrimidin-7-one; (+)-3-
Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl] -2-methyl-2,6
-Dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-
1 (R) -methylethoxy) pyridin-3-yl] -2
-(6-methylpyridin-2-yl) methyl-2,6-
Dihydro-7H-pyrazolo [4,3-d] pyrimidine-
7-one; 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-
3-ethyl-2- (6-methoxypyridin-2-yl)
Methyl-2,6-dihydro-7H-pyrazolo [4,3-
d] pyrimidin-7-one; 5- [2-i-butoxy-
5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -2,3-diethyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7-
ON; 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-
Ethyl-2- [1-pyridin-2-yl) ethyl] 2,
6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; or a pharmaceutically acceptable salt thereof.

A preferred pharmaceutically acceptable salt of sildenafil for use in the present invention is citrate.

Also preferred are those W-designating the United States, which are specifically incorporated herein by reference.
PCT / EP95 published as O95 / 19978
And salts and solvates thereof, which are represented by the general formula:

Embedded image Wherein R ⁰ is hydrogen, halogen or C
_1-6 alkyl; ^{R 1} is _{hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6} alkynyl, halo C
_1-6 represents _{alkyl, C 3-8 cycloalkyl, C 3-8} cycloalkyl _{C 1 -3} alkyl, aryl _{C 1-3} alkyl or heteroaryl _{C 1-3} alkyl; R
² is an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine, or an optionally substituted monocyclic aromatic ring bonded to the rest of the molecule through one of the benzene ring carbon atoms. Bicyclic ring

Embedded image Here, the fused ring A is a 5- or 6-membered ring which may be saturated or partially or completely unsaturated, and may be arbitrarily selected from carbon atoms and oxygen, sulfur and nitrogen. Containing good one or two heteroatoms.
And R ³ represents hydrogen or C _1-3 alkyl, or R ¹ and R ³ are both 3- or 4-
Represents a membered alkyl or alkenyl chain].

Compounds having the general formula Ia (also WO
95/19978), a preferred subset of the general formula:

Embedded image Wherein R ⁰ represents hydrogen, halogen or C _1-6 alkyl; R ¹ is hydrogen, C _1-6 alkyl, haloC
_{Represents 1-6} alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-3 alkyl, aryl C _1-3 alkyl or heteroaryl C _1-3 alkyl; and R ² is benzene, thiophene, An optionally substituted monocyclic aromatic ring selected from furan and pyridine, or an optionally substituted bicyclic ring linked to the rest of the molecule via one of the benzene ring carbon atoms

Embedded image Here, the fused ring A is a 5- or 6-membered ring which may be saturated or partially or completely unsaturated, and may be arbitrarily selected from carbon atoms and oxygen, sulfur and nitrogen. Containing good one or two heteroatoms.
Represents].

Specific compounds falling within the general formula (I) are (6R, 12aR) -2,3,6,7,12,12
a-Hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) -pyrazino [2 ', 1': 6
1] pyrido [3,4-b] indole-1,4-dione.

Preferred potassium channel openers include nicorandil, diazoxide, chromokalim, levocromakalim (lev
crokalim), pinacidil, remacarim (l
emakalim) and minoxidil and pharmaceutically acceptable salts or isomers thereof. Particularly preferred potassium channel openers include nicorandil, diazoxide and minoxidil. Preferred specific multidrugs include:
Sildenafil or a pharmaceutically acceptable salt thereof, especially any of these in combination with citrate. Most preferred is sildenafil citrate in combination with nicorandil. Various potassium channel openers are disclosed in US Pat.
4,867; 5,466,712; 5,403,8
No. 53; 5,403, 854; 5, 397, 790
Nos. 5,401,753; 5,872,139; and 5,905,156, the teachings of which are incorporated herein by reference.

Particular multidrug combinations of potassium channel openers and cGMP enhancers useful in the present invention include any potassium channel opener in combination with sildenafil. Preference is given to multidrug combinations of potassium channel openers and sildenafil, in particular sildenafil citrate, containing any of the previously mentioned ones.

CG useful in the present invention as a cGMP elevating agent
MP PDE inhibitors can be broadly selected from any of those already known in the art or subsequently discovered and / or subsequently developed. Proper cGMP PD
E inhibitors include those disclosed in any of the following US patents, all of which are incorporated herein by reference: US Pat.
5-substituted pyrazolo [4,3-d] pyrimidin-7-ones disclosed in U.S. Pat. No. 4,634,706.
No. 4,783,532, 5,498,819,
A glyceolic acid derivative disclosed in any of 5,532,369, 5,556,975 and 5,616,600; 2-glyceric acid derivative disclosed in U.S. Pat. No. 4,885,301. Phenylpurinone derivatives; phenylpyridone derivatives disclosed in US Pat. No. 5,254,571; US Pat.
US Patent No. 5,075,310; US Patent No. 5,162,316; US Patent No. 5,162,316; US Patent No. 5,075,310; US Patent No. 5,162,316; 5,073,
No. 559; purine compounds disclosed in US Pat.
Quinazoline derivatives disclosed in US Pat. No. 47,875; phenylpyrimidone derivatives disclosed in US Pat. No. 5,118,686; imidazo disclosed in US Pat. Nos. 5,055,465 and 5,166,344. Quinoxalinone derivatives or aza analogs thereof; US Pat. No. 5,29
Phenylpyrimidone derivatives disclosed in U.S. Pat. No. 0,933;
U.S. Pat. No. 5,436,233 or 5,439,8
4-aminoquinazoline derivatives disclosed in U.S. Pat. No. 95; 4,5-dihydro-4-oxo-pyrrolo [1,2-a] quinoxaline derivatives disclosed in U.S. Pat. No. 5,405,847; U.S. Pat. Polycyclic guanine derivatives disclosed in U.S. Patent No. 5,576,322.
Heterocyclic compounds disclosed in U.S. Pat.
Quinazoline derivatives disclosed in U.S. Patent No. 60,615; and 6-heterocycleyl pyrazolo [3,4-d] pyrimidine- disclosed in U.S. Patent No. 5,294,612.
4-one.

Other disclosures of cGMP PDE inhibitors include the following, all of which are incorporated herein by reference: European Patent Application (EPA) 0428268; European Patent Application 0
442204; International Patent Application WO 94/19351; Application / Japanese Patent Application No. 5-222000;
uropean Journal Of Pharmacology), 251 , (1994), 1;
And International Patent Application WO 94/22855.

The potassium channel opening activity of a compound, and thus its suitability for use in the present invention, can be determined using a number of conventional assays in vitro.
Potassium channel openers are available from Quast, B
rit. J. Pharmac., 91, 569-578 (1987) or by a similar method, with cell membranes as indicated by their effects on various smooth muscle preparations at concentrations ranging from 1 to 500 nM. 2 shows relevant potassium channel opening activities.

The cGMP PDE inhibition of a compound can also be measured by standard assays known in the art, for example, as disclosed in US Pat. No. 5,250,534, which is incorporated herein by reference. Can be. cAM
Compounds that are selective inhibitors of cGMPPDE relative to PPDE are preferred, and methods for measuring such compounds are also taught in US Patent No. 5,250,534. Particularly preferred are compounds that selectively inhibit the PDE _V isoenzyme disclosed in the aforementioned PCT / EP94 / 01580 published as WO 94/28902.

[0043]

DETAILED DESCRIPTION OF THE INVENTION As disclosed above, the individual compounds of a combination drug useful in the present invention are usually administered separately by their own conventional and known routes,
In some cases, the route of administration may be different. In a preferred embodiment, usually the time of administration is such that both the potassium channel opener and the cGMP-elevating agent are both at or near the same time reaching maximal pharmacokinetic effects. The route of administration may be oral, parenteral via topical intracavernous or intraurethral injection, or transdermal, such as by topically applying the active ingredient in a gel or other such formulation to the penis. It may be any known in the art. Each component is usually combined with a pharmaceutically acceptable excipient, diluent or carrier, such as tablets, capsules, lozenges for oral administration.
ge), troches, elixirs, solutions or suspensions, for parenteral administration, in suitable injection vehicles, or for topical application, as lotions, ointments or creams. It can be formulated as is known in the art. In a preferred embodiment, the cGMP-elevating agent and the potassium channel opener are each orally co-administered together or separately.

The exact dosage of each component administered will, of course, vary depending on the particular component being prescribed, the subject being treated,
It depends on the severity of impaired or female sexual dysfunction, the mode of administration and the judgment of the prescribing physician. Therefore, due to inter-patient variability, the doses given below are guidelines and it is possible that a physician will adjust the dose of the compound to achieve a treatment that the physician deems appropriate for the male or female patient. it can. In considering the degree of treatment desired, a physician must balance a variety of factors, such as the age of the patient and the presence of other diseases or conditions (eg, cardiovascular disease). Usually, the cGMP-elevating agent will be from 0.5 to 200 mg per day, preferably from 5 to 125 mg per day, more preferably from 25 to 100 mg per day.
Administer in the range of g. The potassium channel opener is usually administered in an amount of 0.01 mg to 50 mg per day, preferably 0.5 to 10 mg per day.
If the cGMP-elevating agent is a prostaglandin, it is usually administered by intracavernous injection in an amount of 1 ng to 100 μg per day or intraurethrally in an amount of 100 μg to 2 mg per day. Usually, the volume to be injected is usually not more than 1 ml. The carrier or diluent is typically a sterile saline solution or other physiologically acceptable salt solution. Oral administration of prostaglandins is also possible. Japanese Journal of U
rology), 83 (10): 1655-1661, (1992).

As previously disclosed, a multidrug combination of a cGMP elevating agent and a potassium channel opener can be administered as a composition. Thus, the compounds of the present invention will usually be administered in any conventional oral, parenteral, rectal or transdermal dosage form, also with pharmaceutically acceptable excipients, diluents or carriers. it can.

For oral administration, the pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Starch, preferably potato or tapioca starch, and various disintegrants such as certain complex silicates, and sodium citrate, calcium carbonate and calcium phosphate with binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. Tablets containing such various excipients are used. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tableting purposes. Solid compositions of a similar type are also used as excipients for filling soft and hard gelatin capsules, and preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. If aqueous suspensions and / or elixirs are desired for oral administration, various sweetening or flavoring agents, coloring agents, emulsifying and / or suspending agents and water, ethanol, propylene glycol, glycerin and the like The compounds of the present invention can be combined with diluents, such as various combinations of

For parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol as well as sterile aqueous solutions of the corresponding water-soluble salts can be used.
Such aqueous solutions can be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this connection, the sterile aqueous medium employed can be readily obtained by standard techniques well known to those skilled in the art.

For transdermal (eg, topical) administration purposes, diluted or sterilized aqueous or partially aqueous solutions (usually about 0.
Prepare a parenteral solution similar to that described above, otherwise 1-5% concentration).

Methods for preparing various pharmaceutical compositions with a predetermined amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in the art. An example of a method of preparing a pharmaceutical composition is described in Remington's Pharmaceutical Science.
s ), Mac Publishing Company
ing Company), Easter, Pa., 15th edition (19
See 75).

[0050]

General Examples Procedures Multidrug combinations of potassium channel openers and cGMP-elevating agents, such as cGMP PDE inhibitors, can be tested in vivo in either the Beagle dog or monkey model. The following description is
Regarding monkeys, those skilled in the art will readily recognize that this test can be equally applied and adapted to Beagle dogs.

Mature adult male monkeys having a body weight in the range of 4 to 8 kg, typically Cercopith
ecus aethios (green monkey) or Ma
caca fasciculata (cynomolo)
gous, cynomolgus monkey). Diazepam (2.5 mg), ketamine chloride (20 intramuscular injections)
anesthetize the animals with μg / kg, and add if appropriate)
The test compound dissolved in saline is given through the corpus cavernosum (0.3 ml). The animal is supine, the penis is extended, and a rubber band is placed around the base of the penis root so that the hemostat is in place for 3 minutes after injection. The solution was injected into one of the corpus cavernosum via a 27G needle,
After 5, 30, 60 and 180 minutes, penile swelling (increased volume) and firmness are estimated visually and by palpitations. To determine the threshold effect using injection solutions, a series of animals are used to cover the appropriate volume range of test compound.

Also, a potassium channel opener and c
Multidrug combinations of GMP-elevating agents can also be tested clinically, typically orally, in human and animal models. Each compound is administered alone and at different times to a population of male patients, and the Rigiscan Clinical etiology of stiffness and swelling in conjunction with the International Index of Erectile Function (IIEF) questionnaire assessing patient and partner satisfaction. Valuation (Rigiscan Clinical Evaluation) parameters
(Kaneko et al., J. Urol. 136, 1026-1029 (1986);
And Ogric et al., J. Urol., 154, 1356-135
9 (1995)), each compound is administered in an amount that produces little or no response, typically less than 50% response. Administering each compound alone means administering one compound followed by a second time after allowing an appropriate time for the washout of the first compound. After a washout time for each compound administered alone, the compounds are pharmacokinetically acting, preferably in a manner such that the pharmacokinetic effects of the peaks attributable to each occur simultaneously. Is co-administered. Co-administration is assessed by the Rigiscan parameters and the IIEF questionnaire described above, thereby providing a basis for comparing the effects of each administration alone and co-administration and showing a synergistic effect.

The compounds of the invention and the combination drug are usually administered as a convenient formulation. The following formulation examples are for illustrative purposes only and do not limit the scope of the invention.

【Example】

In the following formulations, the {active ingredient}
Means a compound of the invention. Formulation 1: Gelatin capsules Hard gelatin capsules were prepared using:
Was: Ingredient Amount (mg / capsule)  Active ingredient 0.25-100 Starch, NF 0-650 Starch flowing powder 0-50Silicone liquid 350 centistoke 0-15  

A tablet formulation was prepared using the following ingredients:
Formulation 2: tablets Ingredient Amount (mg / tablet)  Active ingredient 0.25-100 Cellulose, microcrystal 200-650 Silicon dioxide, smoked 10-650Stearic acid 5-15  

The ingredients were mixed and compressed to form tablets.

Or 0.25-100 mg each
Tablets containing the active ingredient of were prepared as follows: Formulation 3: Tablets Ingredient Amount (mg / tablet)  Active ingredient 0.25-100 Starch 45 Cellulose, microcrystal 35 Polyvinylpyrrolidone (as 10% aqueous solution) 4 Sodium carboxymethylcellulose 4.5 Magnesium stearate 0.5Talc 1 

The active ingredient, starch and cellulose were mixed with a No. 45 mesh U.S.A. S. Pass through sieve and mix thoroughly. The resulting powder was mixed with a solution of polyvinylpyrrolidone, and then a No. 14 mesh U.S.A.
S. Passed through a sieve. The granules thus produced are
Dry at 50 ° -60 ° C. and use a No. 18 mesh U.S.A. S.
Passed through a sieve. No. 60 U.S.A. in advance. S. The sodium carboxymethyl starch, magnesium stearate, and talc that had passed through the sieve were then added to the granules, mixed, and compressed on a tablet machine to give tablets.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 487/04 147 C07D 487/04 147 F Term (Reference) 4C050 AA01 BB05 BB08 CC08 EE04 FF02 GG03 HH04 4C084 AA20 MA02 NA05 NA14 ZA811 ZC011 ZC022 ZC202 4C086 AA01 CB05 CB09 DA01 GA14 MA02 MA04 NA05 NA14 ZA81 ZC01 ZC02 ZC20

Claims (66)

[Claims] 1. A method of treating disability, comprising: an effective amount of a compound selected from potassium channel openers for a patient in need of such treatment; and cGMP.
Such a method, comprising co-administering a compound that increases the level. 2. The method according to claim 1, wherein the cGMP-elevating agent is cGMP PDE.
The method as defined in claim 1, which is an inhibitor. 3. The method as defined in claim 1, wherein said cGMP elevating agent is a prostaglandin. 4. The method of claim 1, wherein the cGMP PDE inhibitor is cGMP.
3. A method as defined in claim 2 which is selective for the MP PDE _V isoenzyme. 5. The method as defined in claim 4, wherein said cGMP PDE inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. 6. The salt according to claim 5, wherein the salt is a citrate.
The method as clarified in. 7. The cGMP PDE inhibitor has the structure: A method as defined in claim 2, comprising: 8. The method according to claim 8, wherein the cGMP PDE inhibitor is 3-
Ethyl-5- [2- (2-methoxyethoxy) -5
(4-Methylpiperazin-1-ylsulfonyl) pyridin-3-yl] -2- (pyridin-2-yl) methyl-
2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2) 2-methoxyethoxy) Pyridin-3-yl] -2- (pyridine-
2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 3-ethyl-5
-[5- (4-Ethyl-4-oxidepiperazine-1-
Ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7- ON; 5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-n-propyl-2-
(Pyridin-2-yl) methyl-2,6-dihydro-7
H-pyrazolo [4,3-d] pyrimidin-7-one; 5
-[5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -3-n-propyl-2- (pyridin-2-yl)
Methyl-2,6-dihydro-7H-pyrazolo [4,3-
d] pyrimidin-7-one; (+)-3-ethyl-5-
[5- (4-ethylpiperazin-1-ylsulfonyl)
-2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl] -2-methyl-2,6-dihydro-
7H-pyrazolo [4,3-d] pyrimidin-7-one;
3-ethyl-5- [5- (4-ethylpiperazine-1-
Ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl] -2- (6-methylpyridin-2-yl) methyl-2,6-dihydro-7
H-pyrazolo [4,3-d] pyrimidin-7-one; 5
-[2-ethoxy-5- (4-ethylpiperazine-1-
Ylsulfonyl) pyridin-3-yl] -3-ethyl-
2- (6-methoxypyridin-2-yl) methyl-2,
6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- [2-i-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-
Yl] -2,3-diethyl-2,6-dihydro-7H-
Pyrazolo [4,3-d] pyrimidin-7-one; 5-
[2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2
-[1-pyridin-2-yl) ethyl] 2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; or a pharmaceutically acceptable salt of the compound, A method as defined in claim 2. 9. The method according to claim 9, wherein the potassium channel opener is
Nicorandil, chromokalim
m), levcromakalim
m), lemacalim, pinacidil, diazoxide and minoxidil or a pharmaceutically acceptable salt thereof, or a process as defined in claim 1. 10. The method as defined in claim 9, wherein said potassium channel opener is nicorandil or a pharmaceutically acceptable salt thereof. 11. The method of claim 1, wherein said first compound is nicorandil or a pharmaceutically acceptable salt thereof, and said second compound is sildenafil or a pharmaceutically acceptable salt thereof. The method as clarified in item 1. 12. The method as defined in claim 11, wherein said first compound is nicorandil and said second compound is sildenafil citrate. 13. The method as defined in claim 1, wherein (1) and (2) are each administered orally. 14. The method as defined in claim 1, wherein (1) and (2) are administered together as one composition. 15. The method as defined in claim 1, wherein (1) and (2) are administered separately. 16. (1) a first compound selected from potassium channel openers; (2) a second compound that increases cGMP levels; and (3) a pharmaceutically acceptable excipient or diluent. Or a therapeutically effective amount of a pharmaceutical composition comprising a carrier. 17. The cGMP-elevating agent is cGMP PD.
17. A composition as defined in claim 16 which is an E inhibitor. 18. The composition as defined in claim 17, wherein said cGMP elevating agent is a prostaglandin. 19. The method of claim 19, wherein the cGMP PDE inhibitor is c
18. The method of claim 17, which is selective for GMP PDE _V isoenzyme.
Composition as specified in. 20. The composition as defined in claim 19, wherein said cGMP PDE inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. 21. The composition as defined in claim 20, wherein said salt is a citrate. 22. The cGMP PDE inhibitor has a structure Or a pharmaceutically acceptable salt thereof, as defined in claim 16. 23. The cGMP PDE inhibitor comprises 3
-Ethyl-5- [2- (2-methoxyethoxy) -5-
(4-Methylpiperazin-1-ylsulfonyl) pyridin-3-yl] -2- (pyridin-2-yl) methyl-
2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2) 2-methoxyethoxy) Pyridin-3-yl] -2- (pyridine-
2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 3-ethyl-5
-[5- (4-Ethyl-4-oxidepiperazine-1-
Ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7- ON; 5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-n-propyl-2-
(Pyridin-2-yl) methyl-2,6-dihydro-7
H-pyrazolo [4,3-d] pyrimidin-7-one; 5
-[5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -3-n-propyl-2- (pyridin-2-yl)
Methyl-2,6-dihydro-7H-pyrazolo [4,3-
d] pyrimidin-7-one; (+)-3-ethyl-5-
[5- (4-ethylpiperazin-1-ylsulfonyl)
-2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl] -2-methyl-2,6-dihydro-
7H-pyrazolo [4,3-d] pyrimidin-7-one;
3-ethyl-5- [5- (4-ethylpiperazine-1-
Ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl] -2- (6-methylpyridin-2-yl) methyl-2,6-dihydro-7
H-pyrazolo [4,3-d] pyrimidin-7-one; 5
-[2-ethoxy-5- (4-ethylpiperazine-1-
Ylsulfonyl) pyridin-3-yl] -3-ethyl-
2- (6-methoxypyridin-2-yl) methyl-2,
6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- [2-i-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-
Yl] -2,3-diethyl-2,6-dihydro-7H-
Pyrazolo [4,3-d] pyrimidin-7-one; 5-
[2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2
-[1-pyridin-2-yl) ethyl] 2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; or a pharmaceutically acceptable salt of the compound, A composition as described in claim 16. 24. The potassium channel opener is selected from the group consisting of nicorandil, cromocarim, levcromakalim,
17. A composition as defined in claim 16, wherein the composition is selected from the group consisting of remacarim, pinacidil, diazoxide, and minoxidil or a pharmaceutically acceptable salt thereof. 25. The composition as defined in claim 24, wherein said potassium channel opener is nicorandil or a pharmaceutically acceptable salt thereof. 26. The method of claim 1, wherein the first compound is nicorandil or a pharmaceutically acceptable salt thereof, and the second compound is sildenafil or a pharmaceutically acceptable salt thereof. Item 18. A composition as defined in item 16. 27. The composition as defined in claim 16, wherein said first compound is nicorandil and said second compound is sildenafil citrate. 28. A method for achieving a therapeutically effective level of inability to treat synergy, comprising: providing a mammal in need of such treatment with (1) an amount of a first amount selected from potassium channel openers. Compound; and (2) cGMP
A certain amount of a second compound selected from compounds that elevate the level (where a predetermined amount of the first compound alone and a predetermined amount of the second compound alone provide a therapeutically effective level of inability to treat synergy Is insufficient to achieve, but the combined effect of the predetermined amounts of the first and second compounds is less than the sum of the levels of therapeutic effect of the disability treatment that can be achieved with the individual amounts of the first and second compounds. Large)). 29. The cGMP increasing agent is cGMP PD.
29. A method as defined in claim 28 which is an E inhibitor. 30. The method as defined in claim 29, wherein said cGMP elevating agent is a prostaglandin. 31. The cGMP PDE inhibitor comprises c
30. It is selective for GMP PDE _V isoenzyme.
The method as clarified in. 32. The method as defined in claim 31, wherein said cGMP PDE inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. 33. The method as defined in claim 32, wherein said salt is a citrate. 34. The cGMP PDE inhibitor has the structure Or a pharmaceutically acceptable salt thereof, as defined in claim 29. 35. The cGMP PDE inhibitor, wherein
-Ethyl-5- [2- (2-methoxyethoxy) -5-
(4-Methylpiperazin-1-ylsulfonyl) pyridin-3-yl] -2- (pyridin-2-yl) methyl-
2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2) 2-methoxyethoxy) Pyridin-3-yl] -2- (pyridine-
2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 3-ethyl-5
-[5- (4-Ethyl-4-oxidepiperazine-1-
Ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7- ON; 5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-n-propyl-2-
(Pyridin-2-yl) methyl-2,6-dihydro-7
H-pyrazolo [4,3-d] pyrimidin-7-one; 5
-[5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -3-n-propyl-2- (pyridin-2-yl)
Methyl-2,6-dihydro-7H-pyrazolo [4,3-
d] pyrimidin-7-one; (+)-3-ethyl-5-
[5- (4-ethylpiperazin-1-ylsulfonyl)
-2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl] -2-methyl-2,6-dihydro-
7H-pyrazolo [4,3-d] pyrimidin-7-one;
3-ethyl-5- [5- (4-ethylpiperazine-1-
Ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl] -2- (6-methylpyridin-2-yl) methyl-2,6-dihydro-7
H-pyrazolo [4,3-d] pyrimidin-7-one; 5
-[2-ethoxy-5- (4-ethylpiperazine-1-
Ylsulfonyl) pyridin-3-yl] -3-ethyl-
2- (6-methoxypyridin-2-yl) methyl-2,
6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- [2-i-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-
Yl] -2,3-diethyl-2,6-dihydro-7H-
Pyrazolo [4,3-d] pyrimidin-7-one; or 5- [2-ethoxy-5- (4-ethylpiperazine-
1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [1-pyridin-2-yl) ethyl] 2,6-
Dihydro-7H-pyrazolo [4,3-d] pyrimidine-
30. The method as defined in claim 29, wherein the compound is 7-one; or a pharmaceutically acceptable salt of the compound. 36. The first compound is nicorandil,
29. The method as defined in claim 28, wherein the method is selected from the group consisting of cromocarim, rebucromakalim, remacalim, pinacidil, diazoxide and minoxidil, or a pharmaceutically acceptable salt thereof. 37. The method as defined in claim 36, wherein said potassium channel opener is nicorandil or a pharmaceutically acceptable salt thereof. 38. A method as defined in claim 28 comprising (1) nicorandil; and (2) sildenafil or a pharmaceutically acceptable salt thereof. 39. The potassium channel opener (1) is nicorandil or a pharmaceutically acceptable salt thereof, and (2) is sildenafil citrate, as defined in claim 28. Method. 40. A fixed amount of a first compound selected from the group consisting of (1) a potassium channel opener; and (2) a fixed amount of a second compound selected from a compound that increases the cGMP level (here, a predetermined amount of the first compound). Although the compound alone and the predetermined amount of the second compound alone are each insufficient to achieve a therapeutically effective level of inability to treat synergy, the amounts of the first and second compounds may not be sufficient. And the pharmaceutically acceptable excipients, diluents) wherein the effect of the composition comprising is greater than the sum of the levels of therapeutic effect of the disability treatment achievable with the individual amounts of the first and second compounds). Or a composition comprising a carrier. 41. The cGMP increasing agent is cGMP PD.
41. A composition as defined in claim 40 which is an E inhibitor. 42. The composition as defined in claim 41, wherein said cGMP elevating agent is a prostaglandin. 43. The cGMP PDE inhibitor comprises c
42. The GMP PDE _V isoenzyme is selective.
Composition as specified in. 44. The composition as defined in claim 43, wherein said cGMP PDE inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. 45. The composition as defined in claim 44, wherein said salt is a citrate. 46. The cGMP PDE inhibitor has the structure 41. A composition as defined in claim 40, having the formula: or a pharmaceutically acceptable salt thereof. 47. The cGMP PDE inhibitor, wherein
-Ethyl-5- [2- (2-methoxyethoxy) -5-
(4-Methylpiperazin-1-ylsulfonyl) pyridin-3-yl] -2- (pyridin-2-yl) methyl-
2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2) 2-methoxyethoxy) Pyridin-3-yl] -2- (pyridine-
2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 3-ethyl-5
-[5- (4-Ethyl-4-oxidepiperazine-1-
Ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7- ON; 5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-n-propyl-2-
(Pyridin-2-yl) methyl-2,6-dihydro-7
H-pyrazolo [4,3-d] pyrimidin-7-one; 5
-[5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -3-n-propyl-2- (pyridin-2-yl)
Methyl-2,6-dihydro-7H-pyrazolo [4,3-
d] pyrimidin-7-one; (+)-3-ethyl-5-
[5- (4-ethylpiperazin-1-ylsulfonyl)
-2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl] -2-methyl-2,6-dihydro-
7H-pyrazolo [4,3-d] pyrimidin-7-one;
3-ethyl-5- [5- (4-ethylpiperazine-1-
Ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl] -2- (6-methylpyridin-2-yl) methyl-2,6-dihydro-7
H-pyrazolo [4,3-d] pyrimidin-7-one; 5
-[2-ethoxy-5- (4-ethylpiperazine-1-
Ylsulfonyl) pyridin-3-yl] -3-ethyl-
2- (6-methoxypyridin-2-yl) methyl-2,
6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- [2-i-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-
Yl] -2,3-diethyl-2,6-dihydro-7H-
Pyrazolo [4,3-d] pyrimidin-7-one; 5-
[2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2
-[1-pyridin-2-yl) ethyl] 2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; or a pharmaceutically acceptable salt of the compound, 42. A composition as described in claim 41. 48. The first compound is nicorandil,
41. A composition as defined in claim 40, wherein the composition is selected from the group consisting of cromocarim, reb cromakalim, remacalim, pinacidil, diazoxide, and minoxidil, or a pharmaceutically acceptable salt thereof. 49. The composition as defined in claim 48, wherein said potassium channel opener is nicorandil or a pharmaceutically acceptable salt thereof. 50. The method, wherein the first compound is nicorandil or a pharmaceutically acceptable salt thereof, and the second compound is sildenafil or a pharmaceutically acceptable salt thereof. 50. A composition as defined in paragraph 49. 51. The composition as defined in claim 50, wherein said first compound is nicorandil and said second compound is sildenafil citrate. 52. A therapeutically effective amount of (1) a compound selected from potassium channel openers and a pharmaceutically acceptable excipient, diluent or carrier in a first dosage form. A first composition; (2) a second dosage form comprising a compound selected from a drug that increases cGMP levels, and a pharmaceutically acceptable excipient, diluent or carrier. A second composition;
And (3) a kit comprising parts for containing the first and second dosage forms. 53. The kit as defined in claim 52, wherein said second composition comprises a cGMP PDE inhibitor, a cGMP elevating agent. 54. The cGMP PDE inhibitor comprises c
54. It is selective for the GMP PDE _V isoenzyme.
Kit as clarified in. 55. The kit as defined in claim 54, wherein said cGMP PDE inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. 56. A kit as defined in claim 55, wherein said salt is a citrate. 57. The cGMP PDE inhibitor has the structure 53. A kit as defined in claim 52 having or a pharmaceutically acceptable salt thereof. 58. The cGMP PDE inhibitor, wherein 3
-Ethyl-5- [2- (2-methoxyethoxy) -5-
(4-Methylpiperazin-1-ylsulfonyl) pyridin-3-yl] -2- (pyridin-2-yl) methyl-
2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2) 2-methoxyethoxy) Pyridin-3-yl] -2- (pyridine-
2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 3-ethyl-5
-[5- (4-Ethyl-4-oxidepiperazine-1-
Ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7- ON; 5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-n-propyl-2-
(Pyridin-2-yl) methyl-2,6-dihydro-7
H-pyrazolo [4,3-d] pyrimidin-7-one; 5
-[5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -3-n-propyl-2- (pyridin-2-yl)
Methyl-2,6-dihydro-7H-pyrazolo [4,3-
d] pyrimidin-7-one; (+)-3-ethyl-5-
[5- (4-ethylpiperazin-1-ylsulfonyl)
-2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl] -2-methyl-2,6-dihydro-
7H-pyrazolo [4,3-d] pyrimidin-7-one;
3-ethyl-5- [5- (4-ethylpiperazine-1-
Ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl] -2- (6-methylpyridin-2-yl) methyl-2,6-dihydro-7
H-pyrazolo [4,3-d] pyrimidin-7-one; 5
-[2-ethoxy-5- (4-ethylpiperazine-1-
Ylsulfonyl) pyridin-3-yl] -3-ethyl-
2- (6-methoxypyridin-2-yl) methyl-2,
6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- [2-i-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-
Yl] -2,3-diethyl-2,6-dihydro-7H-
Pyrazolo [4,3-d] pyrimidin-7-one; 5-
[2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2
-[1-pyridin-2-yl) ethyl] 2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; or a pharmaceutically acceptable salt of the compound, A kit as defined in claim 53. 59. The first compound is nicorandil,
53. A kit as defined in claim 52, wherein the kit is selected from the group consisting of cromocarim, reb cromakalim, remacalim, pinacidil, diazoxide and minoxidil, or a pharmaceutically acceptable salt thereof. 60. The kit as defined in claim 59, wherein said first compound is nicorandil or a pharmaceutically acceptable salt thereof. 61. (1) is nicorandil or a pharmaceutically acceptable salt thereof, and (2)
55. A kit as defined in claim 52, wherein is is sildenafil or a pharmaceutically acceptable salt thereof. 62. The kit as defined in claim 61, wherein said sildenafil salt is citrate. 63. A kit as defined in claim 61, wherein (1) and (2) are each administered orally. 64. A kit as defined in claim 52 adapted for the treatment of male erectile dysfunction or female sexual dysfunction. 65. A method of treating female sexual dysfunction, comprising administering to a patient in need of such treatment an effective amount of: a compound selected from potassium channel openers and a compound that increases cGMP levels. Said method comprising co-administering 66. A method for achieving a therapeutically effective level of female sexual dysfunction treatment for synergism, comprising the steps of: providing a mammal in need of such treatment with (1) a potassium channel opener; An amount of the first compound; and (2) an amount of a second compound selected from compounds that increase the cGMP level (where the predetermined amount of the first compound alone and the predetermined amount of the second compound alone include: Although achieving a therapeutically effective level of female sexual dysfunction treatment of synergy is inadequate, the combined effect of the predetermined amounts of the first and second compounds may result in separate amounts of the first and second compounds. The greater than the sum of the levels of therapeutic efficacy of the female sexual dysfunction treatment achievable with the second compound).